Emergence of sequence sensitivity in a hippocampal CA3–CA1 model

Abstract

Recent studies have shown that place cells in the hippocampal CA1 region fire in a sequence sensitive manner. In this study we tested if hippocampal CA3 and CA1 regions can give rise to the sequence sensitivity. We used a two-layer CA3–CA1 hippocampal model that consisted of Hodgkin–Huxley style neuron models. Sequential input signals that mimicked signals projected from the entorhinal cortex gradually modified the synaptic conductances between CA3 pyramidal cells through spike-timing-dependent plasticity (STDP) and produced propagations of neuronal activity in the radial direction from stimulated pyramidal cells. This sequence dependent spatio-temporal activity was picked up by specific CA1 pyramidal cells through modification of Schaffer collateral synapses with STDP. After learning, these CA1 pyramidal cells responded with the highest probability to the learned sequence, while responding with a lower probability to different sequences. These results demonstrate that sequence sensitivity of CA1 place cells would emerge through computation in the CA3 and CA1 regions.

Introduction

Since the discovery of place cells in the rat hippocampus (O’Keefe and Dostrovsky, 1971, O’Keefe and Nadel, 1978), the role of the hippocampus as a cognitive spatial map has attracted large interest. However, subsequent findings have suggested that hippocampal place cells are not providing simple spatial maps. It is reported that when rats visit multiple places, corresponding place cells fire in sequence in a time-compressed manner (Dragoi and Buzsáki, 2006, Skaggs et al., 1996) through theta phase precession (O’Keefe & Recce, 1993). These place cells fire in the same sequence during subsequent sleep (Lee and Wilson, 2002, Skaggs and McNaughton, 1996) suggesting that sequences are stored within the hippocampus and recalled during sleep to be consolidated in the higher cortex as long-term memory.

Recent studies have shown more direct involvement of place cells with sequences. Wood, Dudchenko, Robitsek, and Eichenbaum (2000) have investigated, using a maze that has two loops partly connected to each other, the activity of place cells that have place fields in the part of the maze which is common to both loops. They have shown that 31 out of 33 CA1 place cells fired differently, depending on which of the two loops the rats came from or were going to. This demonstrates that a large amount of CA1 place cells are sensitive to sequences of the past or the future. More recently, Ferbinteanu and Shapiro (2003) have shown that a large portion of rat CA1 place cells is retrospectively sequence-sensitive (sensitive to the sequence of the past) using a “+” shaped maze. Frank, Brown, and Wilson (2000) have compared place cells in the superficial layers of the entorhinal cortex (EC) that give input to the hippocampus, with place cells in the deep layers of the EC that receive output from the hippocampus. They have found that place cells in the deep layer of the EC are more sensitive to sequences than place cells in the superficial layers, suggesting that sequence sensitivity of place cells emerges in the hippocampus.

Varieties of computational models have been proposed to explain sequence learning and recall of place cells. Storages and recalls of sequences through asymmetric recurrent connections between neurons (Tsodyks, Skaggs, Sejnowski, & McNaughton, 1996), particularly in the CA3 area (Jensen and Lisman, 1996a, Jensen and Lisman, 1996b, Levy, 1996, Wallenstein and Hasselmo, 1997, Yamaguchi, 2003) or in reciprocal dentate-CA3 network (Lisman, 1999) have been proposed. Although these models demonstrated that learned sequences were recalled successfully, they did not demonstrate sequence sensitivity of place cells. Recently, Hasselmo and Eichenbaum (2005) proposed a binary model in which place cells responded sensitively to a sequence. In their model, sequences were stored in the EC layer III and information about previous paths was stored as a delayed activity in EC layer II neurons. Convergence of these signals in the CA1 region made sequence-sensitive firing possible. In this paper, we focus on the retrospective sequence sensitivity which is the ability of place cells to fire depending not only on the current position of the animal but also on the places visited in the past. The goal of this study is to test if the hippocampal CA3–CA1 region alone can produce retrospective sequence sensitivity of CA1 place cells, using more physiological hippocampal models, learning rules and input signals.

Hippocampal CA3 and CA1 regions have distinct anatomical and physiological features. The CA3 region has dense excitatory recurrent synaptic connections between pyramidal cells (Li et al., 1994, Tamamaki and Nojyo, 1991). Anatomical and physiological features of the CA3 region support the idea that this area spontaneously generates a theta rhythm (Buzsáki, 2002). Synaptic conductances of recurrent synapses are modified through spike-timing-dependent synaptic plasticity (STDP) (Bi and Poo, 1998, Debanne et al., 1998). These experimental observations imply the possibility of intra-network computation that utilizes spontaneous rhythmic activity and synaptic modification of recurrent connections in the CA3 region.

On the other hand, recurrent connections between CA1 pyramidal cells are not dense (Tamamaki and Nojyo, 1990, Witter and Amaral, 1991). CA1 pyramidal cells are less active compared to CA3 pyramidal cells (Fricker, Verheugen, & Miles, 1999). This suggests that spontaneous activity and its propagation hardly occur in the CA1 region. However, CA1 pyramidal cells receive a large number of excitatory synaptic inputs from CA3 pyramidal cells through Schaffer collaterals. Each CA1 pyramidal cell has 20–30 thousand Schaffer collateral synapses (Li et al., 1994). Synaptic projection from each CA3 pyramidal cell through Schaffer collaterals covers two thirds of the longitudinal extent of the CA1 region (Li et al., 1994). Moreover, conductances for the extensive Schaffer collateral synapses are modified through STDP (Bi and Poo, 1998, Nishiyama et al., 2000). This implies that computation may also be executed in feed-forward synaptic connections from CA3 to CA1.

We developed a CA3–CA1 hippocampal model endowed with the anatomical and physiological aspects mentioned above. Sequential input signals that mimicked signals projected through the perforant path from the EC, were applied to groups of pyramidal cells in the CA3 and CA1 regions. In the CA3 region, this signal modified the synaptic conductances between CA3 pyramidal cells and produced propagations of neuronal activity in the radial direction from stimulated pyramidal cells. The radial propagations of neuronal activity stored the timings of input signals by their radii; earlier and later signals caused larger and smaller ring-shaped neuronal activities, respectively. This firing pattern of the CA3 region was picked up by the conductances of Schaffer collateral synapses through STDP. Accordingly, CA1 pyramidal cells received maximum synaptic input from CA3 and responded with the highest probability when the sequence of input signals was identical to the learned sequence. The response rate was lower when the sequence of input signals was different from the learned sequence. These results demonstrate that anatomical and physiological features of the CA3 and CA1 regions, together with input signals from place cells in the EC, allow CA1 place cells to be sequence sensitive. Some of the results of the present paper have been reported in a conference proceedings (Yoshida & Hayashi, 2004b).